Clinical Biochemistry 40 (2007) 153 – 161

Review
How to estimate GFR-serum creatinine, serum cystatin C or equations?
Stefan Herget-Rosenthal a,⁎, Arend Bökenkamp b , Walter Hofmann c
a
Department of Nephrology, University of Duisburg-Essen, Germany
b
Department of Pediatrics, Vrije Universeit Medical Center, Amsterdam, The Netherlands
c
Institute of Clinical Chemistry and Immunology, Städtisches Klinikum München, Germany
Received 28 April 2006; received in revised form 10 October 2006; accepted 13 October 2006
Available online 21 November 2006

Abstract

Plasma or serum creatinine is the most commonly used diagnostic marker for the estimation of glomerular filtration rate (GFR) in clinical
routine. Due to substantial pre-analytical and analytical interferences and limitations, creatinine cannot be considered accurate. Besides, the
diagnostic sensitivity to detect moderate GFR reduction is insufficient. Equations to estimate GFR based on serum creatinine have been
introduced, which included anthropometric data to compensate for the limitations of creatinine. Most validated and applied are the MDRD and the
Cockcroft–Gault equation for adults, and the Schwartz equation for children. These equations can be calculated at the bedside or issued by the
laboratory and provide accurate GFR estimates from 20 to 60 mL/min/1.73 m2 with good accuracy but moderate to poor bias and precision.
Further limiting is the lack of creatinine reference methods and of calibration material. Lately, the low molecular weight protein cystatin C was
introduced as a GFR estimate superior to creatinine. In particular, serum cystatin C is sensitive to detect mild GFR reduction between 60 and
90 mL/min/1.73 m2. However, no reference method and no uniform calibration material exist for cystatin C either. Further limitations are the effect
of thyroid dysfunction, of high glucocorticoid doses and potentially the presence of cardiovascular diseases on cystatin C levels. To evade these
obstacles and to further improve GFR estimation, cystatin C-based equations have been proposed, which seem to be superior to creatinine-based
ones. However, this issue requires further evaluation. We propose a panel of GFR markers to facilitate the detection of reduced GFR at various
stages and in different populations; this however needs to be extended and refined in the near future. In principle, clinicians should be aware of the
limitations of and cautioned not to overrate estimated GFR by single markers or calculated by equations and should not entirely rely on GFR
estimates to make precise clinical decisions.
© 2006 The Canadian Society of Clinical Chemists. All rights reserved.

Keywords: Chronic kidney disease; Creatinine; Cystatin C; Glomerular filtration rate; MDRD equation

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Measurement of glomerular filtration rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Creatinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Equations estimating GFR based on creatinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Cystatin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Equations estimating GFR based on cystatin C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Comparison between cystatin C and creatinine-based prediction equations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Precision of cystatin C and creatinine-based equations estimating GFR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Summary, recommendations and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

⁎ Corresponding author. Klinik für Nieren-und Hochdruckkrankheiten, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany. Fax: +49 201 723
5633.
E-mail address: stefan.herget-rosenthal@uni-due.de (S. Herget-Rosenthal).

0009-9120/$ - see front matter © 2006 The Canadian Society of Clinical Chemists. All rights reserved.
doi:10.1016/j.clinbiochem.2006.10.014
154 S. Herget-Rosenthal et al. / Clinical Biochemistry 40 (2007) 153–161

Introduction the character of the specific gold standard method used may
have a considerable effect on the result. In the following, all
Chronic kidney disease (CKD) and end-stage renal disease in gold standard methods of GFR measurement are equated for
particular are major health problems worldwide with dramati- simplification as the variability of the published does not permit
cally rising incidence and prevalence. The population with end- correction of these methodological limitations.
stage renal disease in the USA increased from approximately Serum or plasma creatinine is the metabolite most commonly
200,000 in 1991 to 380,000 in 2000, and it has recently been used for this purpose, although several drawbacks have been
predicted to almost double to 710,000 by 2015 [1]. Patients with identified: First, tubular secretion plays an important role in
diabetes and hypertension are particularly affected by this creatinine elimination with declining GFR. Therefore, serum
negative development. However, most patients with CKD are creatinine concentrations can be within the normal range even
only identified or adequately treated with significant delay, with a GFR around 60 mL/min/1.73 m2 resulting in a “creatinine-
which is critical to stop progression of CKD to end-stage renal blind range” [3]. Second, creatinine production varies consider-
disease and to lower the enormous cardiovascular co-morbidity ably intra- and inter-individually [3]. This explains the high
associated with CKD. This development has raised great inter-individual variability of serum creatinine [7], which
concern and has led to the first global definition and precludes a reliable estimation of kidney function from a single
classification of CKD in 2004 by the independent international creatinine measurement without additional patient data. This
Kidney Disease Improving Global Outcome organisation applies to in particular to children, the elderly and severely ill
(KDIGO) [2]. KDIGO recommended two laboratory tests for patients [3].
an earlier detection of CKD: estimation of glomerular filtration Besides these problems relating to creatinine metabolism,
rate, as this is the best estimate of functioning renal mass creatinine measurement is technically difficult. Several different
(eGFR), using the simplified equation derived from the methods have been developed with the Jaffé method being the
Modification of Diet in Renal Disease Study (MDRD), and most commonly used. This assay is hampered by interferences
determination of proteinuria, preferably microalbuminuria, as up to 20% non-creatinine chromogenes (e.g., acetic acid,
corrected for urine creatinine. The recommendations have acetone, pyruvate, glucose, ascorbic acid) are detected [8–10].
been accepted almost worldwide in the nephrological commu- With the development of enzymatic assays, the problem of
nity. The widespread use of eGFR in particular is an important interferences has been reduced but not eliminated [9,11].
step forward, but it necessarily represents a simplification. This Differences in specificity between different assays make compar-
review will present an overview over the potential and ison of creatinine measurements in different laboratories difficult
limitations of the most common endogenous GFR markers [11]. Table 1 provides a non-representative list of reference
and estimations of GFR presently used in clinical practice. materials and methods used by different manufacturers. The
development of a reference method using isotope dilution mass
Measurement of glomerular filtration rate spectrometry has facilitated the measurement of true creatinine
[11]. With this method, it was recognized that the standard assays
Creatinine to measure creatinine in clinical practice yielded systematically
higher readings than this reference method. For all these reasons,
An ideal endogenous marker of glomerular filtration rate the National Kidney Foundation concluded that serum creatinine
(GFR) should be produced at a constant rate and be eliminated should not be used as the sole means to assess the level of renal
exclusively by glomerular filtration [3]. Under such conditions, function level [12].
its steady state serum concentration reflects GFR. The urinary
clearance of inulin is generally regarded the gold standard to
measure GFR [4]. As this method requires continuous Table 1
intravenous infusion and multiple, timed urine collections, Reference material and methods for creatinine determination
and inulin measurement is expensive and not routinely Company Reference material Reference methods
available, it has remained a method for research purposes. Abbott Serum: NIST SRM Gravimetric
Thus, single-injection, single-sample clearances of exogenous Urine: NIST SRM 914
radioactive and non-radioactive markers such as iothalamate Bayer Serum: NIST ID-MS, HPLC
Urine: NIST
and 99mTc DTPA have been introduced to simplify GFR
Beckman Coulter Serum: NIST ID-MS
measurement in day-to-day clinical practice [5,6]. Although Urine: NIST
adequately accurate to meet clinical demands, they are less Biomed Serum: NIST SRM 909b ID-MS
accurate than two- and multiple-sample methods and may give Jaffè with compensation
substantial systematic error in GFR of up to 10–15 mL/min Dade-Behring Serum: NIST SRM 914 ID-MS
Greiner Biochemica Serum: NIST SRM 909b ID-MS
[5,6]. Furthermore, some gold standard GFR measurements
Olympus Diagnostica Serum/urine: NIST SRM 909b ID-MS
feature only moderate precision and some bias, with iothala- Ortho Diagnostica Serum/urine: NIST 914a ID-MS
mate, 99mTc DTPA- and 51Cr-EDTA clearances overestimating Roche Diagnostics Serum: pools ID-MS
inulin clearance [4]. These limitations generally need to be Urine: pools
taken into account when GFR markers or eGFR values are HPLC, high-pressure liquid chromatography; ID-MS, isotope dilution-mass
compared to different “gold standard” measurements of GFR, as spectrometry.
 S. Herget-Rosenthal et al. / Clinical Biochemistry 40 (2007) 153–161 155

Equations estimating GFR based on creatinine [19]. Another difficulty may arise from the discontinuous use of
the k constants in adolescent males and the uncertainty at what
These severe limitations of creatinine prompted research for age to use which constant.
more reliable methods to assess kidney function. By many
clinicians, the measurement of endogenous creatinine clearance Cockcroft–Gault equation:
using timed urine collections is regarded as a workable
substitute for the more accurate clearances with exogenous Creatinine clearance ½mL=min
ð140  age ½yrsÞ  body weight ½kg ð0:85 if femaleÞ
markers. Although this method circumvents the problem of ¼
72  serum creatinine ½mg=dL
differences in creatinine production, it cannot correct for tubular
creatinine secretion, which may increase creatinine excretion ð2Þ
more than two-fold with declining GFR [13,14]. High-dose The Cockcroft–Gault equation features several limitations.
cimetidine administered for several days decreases creatinine Firstly, it actually estimates creatinine clearance and is not
secretion [15], but in patients with advanced renal failure supra- normalized to 1.73 m2 body surface area unlike GFR in other
maximal doses of cimetidine have to be given [14]. Also, pre- equations. As with the Schwartz equation, also the Cockcroft–
treatment with cimetidine significantly delays the time until the Gault equation was developed using an outdated Jaffe assay for
GFR becomes known. Furthermore, the measurement of creatinine measurement and should be re-evaluated when
creatinine clearance critically depends on an accurately timed calculated with current creatinine measurements, which more
and complete urine collection. This is a major problem in closely reflect true creatinine. Finally, it requires accurate body
ambulatory patients and even in a hospital setting. weight, which may not always be available, especially in
For these reasons, researchers have tried to find means to laboratory software to provide routine calculations from serum
calculate eGFR reliably from serum or plasma creatinine creatinine measurements.
without the need for urine collection. To compensate for inter- In 1999, Levey et al. [20] proposed a new equation for eGFR
individual variation in creatinine production, several equations in adults using age, gender, ethnicity, serum creatinine, urea
have been developed which include anthropometric factors as nitrogen and albumin derived from the large MDRD study (thus
ethnicity, gender, age and body size. Typically, these formulae termed MDRD equation). One year later, a simplified version of
were calculated by regression analysis in large reference the original MDRD equation was presented which performed as
populations who underwent a gold standard measurement of well as the original one but required only serum creatinine, age,
GFR. At no additional costs, these eGFR can be calculated at gender and ethnicity [20]:
the bedside or even using the laboratory software provided the
relevant data are reported when ordering the creatinine Simplified MDRD equation:
measurement. Using this approach, the sensitivity to detect
CKD may be markedly improved. Three formulae are widely eGFR½mL=min=1:73m2  ¼ 186:3
used in clinical practice: the Schwartz equation for children and
 ðserum creating ½mg=dLÞ1:154
adolescents [16], the Cockcroft–Gault equation for adults [17]
and, more recently, the equation developed in the large  ðage ½yearsÞ0:203
Modification of Diet in Renal Disease Study (MDRD) [18]:  ð0:742; if femaleÞ
 ð1:210; if African AmericanÞ:
Schwartz equation: ð3Þ

  k  body height½cm The simplified MDRD equation allows the classification

eGFR mL=min=1:73m2 ¼ ð1Þ
Serum creatinine½mg=dL renal function with acceptable precision and requires only
minimal information about the patient. It has therefore been
The constant k is 0.45 for infants and 0.55 for children included as the primary GFR marker in the Practice Guide-
between 2 and 12 years. From puberty, 0.55 applies to females lines for Chronic Kidney Disease, published in 2002 by the
and 0.70 for males after puberty [19]. Unlike in the original Kidney Disease Outcomes Quality Initiative of the National
publication introducing the Schwartz equation, the k constants Kidney Foundation (K/DOQI) and the more recent KDIGO
stated above were determined using modern creatinine measure- guidelines [2,21]. Additionally, the staging of CKD proposed
ment more closely reflecting “true creatinine” and ought to be re- by K/DOQI and KDIGO is based on eGFR by the simplified
calibrated before they are used with other assays [19]. It is MDRD (Table 2) [2,21].
necessary that centers determine their own k constants against Despite many advantages, several limitations of these
gold standard GFR measurements, which is rarely done in equations have been recognized in recent studies additionally
clinical practice, however. Also, k constants largely depend on to those already discussed. In the MDRD study, creatinine was
age and closely connected to this on muscle mass, which is determined by the kinetic Jaffè method, using the Beckman Rate
difficult to assess in the individual patient. Like other equations Jaffe/CX3 Synchron assay [18]. Similar to the Schwartz and
using serum creatinine, it underestimates GFR in children with Cockcroft–Gault equations, substantial error is introduced when
high muscle mass (e.g., athletes) and overestimates GFR in the MDRD equation is used with different creatinine assays or
patients with anorexia, neuromuscular or severe chronic diseases calibrator material [10,22]. Therefore, correction factors to
156 S. Herget-Rosenthal et al. / Clinical Biochemistry 40 (2007) 153–161

Table 2
Classification of stages of chronic kidney disease (CKD) according to K/DOQI guidelines [21]
Stage Designation GFR [mL/min/1.73 m2] Concomitant abnormalities
0 Increased risk of CKD (diabetes, hypertension, etc.) ≥ 90 (with risk factors for CKD)
1 Renal damage with normal or elevated GFR ≥ 90 Albuminuria, proteinuria, haematuria
2 Renal damage with mild reduction of GFR 60–89 Albuminuria, proteinuria, haematuria
3 Moderate reduction of GFR 30–59 Proteinuria, haematuria, anaemia, hypocalcaemia
hyperphosphataemia
4 Severe reduction of GFR 15–29 Proteinuria, haematuria, anaemia, acidosis,
hypocalcaemia, hyperphosphataemia
5 Renal failure <15 or dialysis Uraemia

adjust for different creatinine assays and calibrators are urgently alternative to serum creatinine. Cystatin C is a non-glycated,
required before the MDRD equation can uniformly be used in basic protein with a molecular weight of 13.3 kDa, belonging to
clinical practice [10,11,23]. Consequently, the simplified the superfamily of cystatins [36]. Cystatin C functions as the
MDRD equation was recently recalculated with serum creatinine most important inhibitor of cysteine proteinase and as such is
measurements calibrated to an enzymatic assay, traceable to an produced by all nucleated cells at a constant rate. It is freely
isotope dilution mass spectrometry assay [24]: filtered in the glomerulus. Like other low molecular weight
proteins, it is reabsorbed and catabolized in the proximal tubule.
eGFR½mL=min=1:73m2  ¼ 1:75 There is no tubular secretion and only minimal extrarenal
 ðserum creatinine ½mg=dLÞ1:154 elimination [37]. Therefore, the blood concentration of cystatin
 ðage ½yearsÞ0:203 C depends almost entirely on the GFR and is not substantially
ð0:742; if femaleÞ affected by diet, nutritional status, inflammatory or malignant
ð1:212; if African AmericanÞ diseases [36,38]. Various cross-sectional studies have shown
that cystatin C has greater sensitivity to detect reduced GFR in
This recalculated simplified MDRD equation finally fulfills CKD than creatinine and other low molecular weight proteins
the analytical requirements in regard to the standardized [39–50]. Of note, serum cystatin C concentration increases
creatinine assay but still needs to be validated in other cohorts already with mildly reduced GFR of 70 to 90 mL/min [39,47–
to be widely recommended. Besides the pre-analytical and 49], i.e., in the “creatinine-blind range”. Furthermore, recent
analytical limitations, the MDRD and Cockcroft–Gault equa- longitudinal studies have shown that cystatin C concentrations
tions are unsuitable to estimate GFR in healthy individuals and rise earlier in acute kidney injury on intensive care unit, after
have been shown to markedly underestimate GFR above liver transplantation, cardiac surgery, cisplatin chemotherapy
approximately 60 mL/min/1.73 m2 and to markedly over- and coronary angiography [51–56], following uninephrectomy
estimate GFR below approximately 20 mL/min/1.73 m2 and in [57], and in progressive diabetic nephropathy [32]. First studies
nephrotic range proteinuria [25–29]. The MDRD equation is have demonstrated that serum β-trace protein may be as
not as accurate in non-Caucasian populations, and no equation valuable as cystatin C to detect mildly reduced GFR [58–60].
has been validated for rapid GFR changes as in acute kidney However, these data are too preliminary yet to determine where
injury [30,31]. These limitations reflect the characteristics of the β-trace protein will have its role as a GFR marker in comparison
populations these equations were derived from which cannot to other tests.
per se be extrapolated to other patient groups, changing ratios of Modern, commercially available assays for the determina-
tubular excretion, variability and interferences by non-renal tion of cystatin C concentration in serum or plasma are based on
factors of creatinine at different GFR levels. For instance, the particle-enhanced immuno-nephelometric (“PENIA”; Dade
MDRD study included predominately Caucasian, non-diabetic Behring, Marburg, Germany) or immuno-turbidimetric
patients with a stable GFR of about 40 mL/min/1.73 m2 [18]. (“PETIA”; DAKO, Glostrup, Denmark) techniques [47,61].
Furthermore, the question, which equation performs better is Unfortunately, there is still no uniform reference standard for
not settled yet. Some studies describe a higher accuracy of the the calibration of the two commercially available assays [62].
MDRD equation [32,33] while others report similar perfor- No interfering factors with the measurement have been
mance of the MDRD and the Cockcroft–Gault equation described for cystatin C besides excessively elevated rheuma-
[34,35]. toid factor in vitro [63]. There are no relevant differences of
reference values for men or women. In healthy children, the
Cystatin C cystatin C concentration stabilizes from the second year of life
and the reference range is identical to adults [64]. Higher
For decades, low molecular weight proteins such as β2- cystatin C concentrations in infants and the elderly are related to
microglobulin, α1-microglobulin, cystatin C and most recently decreased kidney function in these age groups [64,65]. The
β-trace protein have been recognized as potential endogenous performance of cystatin C as a marker of GFR has been studied
markers of GFR. Cystatin C in particular has received much in many patient populations such as children [39], type I and
attention over the last decade and appears to be a promising type II diabetics [40,48,66,67], mild to moderate CKD of non-
 S. Herget-Rosenthal et al. / Clinical Biochemistry 40 (2007) 153–161 157

diabetic origin [47], renal transplant recipients [41], patients tion, smoking, older age and male gender all of which are
with severe liver [42,68] or neuromuscular disease [46,50], associated with increased cystatin C concentrations in large
tumour patients [43,44] and pregnant women with pre- epidemiological studies in healthy populations [88,89]. As none
eclampsia [45]. Several authors have documented the discre- of these studies included a gold standard measurement of kidney
pancy between increased cystatin C concentrations compared to function, it is presently unknown if the association between
creatinine in older patients [65,69,70]. The vast majority of cystatin C and cardiovascular disease merely reflects early stages of
authors concluded that cystatin C performed better than CKD [90].
creatinine and even better than equations estimating GFR
based on creatinine as a GFR marker [40,48,71,72]. Besides Equations estimating GFR based on cystatin C
these characteristics described, the lower variability of mea-
surements, the shorter half life and the lower distribution Although cystatin C facilitates the recognition of incipient
volume of cystatin add to the superiority of serum cystatin C as CKD without the need for correction for age and anthropo-
a GFR marker in comparison to serum creatinine [73–77]. The metric data, several groups have recently developed equations
latter two characteristics may especially contribute to the to calculate eGFR from serum cystatin C using similar
superiority of serum cystatin C as a marker to detect acute approaches as has been described for creatinine. Besides the
changes in GFR as in acute kidney injury. The higher accuracy lack of a uniform reference standard for the calibration of
of cystatin C in single studies was confirmed by a recent meta- cystatin C, the immuno-turbidimetric assay was re-calibrated in
analysis [78]. However, this is not undisputed, as some other 1999 confining the use of some earlier equations with the
studies showed that serum cystatin C was equal but not superior current assay [39]. There have been numerous equations
to serum creatinine in the detection of renal impairment [79,80]. published to calculate eGFR from serum cystatin C which are
With increasing clinical experience, several limitations as to the listed in Table 3 [35,39,40,49,91–97]. Unlike the MDRD
role of cystatin C as a GFR marker have been observed: Untreated equation, which was calculated from a data set of 1628 patients
hyperthyroidism is associated with mildly elevated and hypothyr- in a multicenter study, cystatin C-based equations were
oidism with mildly reduced serum cystatin C which normalizes in generated and validated in smaller samples in single center
the euthyroid state [81]. Several studies have demonstrated that settings using different gold standard measurements for GFR.
high doses of glucocorticoids increase cystatin C concentrations This partially explains the variation between individual
following solid organ transplantation [82,83]. Finally, several large equations (Table 3). Similar to the MDRD equations, most
epidemiological studies have observed an association between cystatin C-based equations were calculated based on linear
mild elevations of serum cystatin C and increased cardiovascular regression models between the reciprocal of cystatin C or log
and overall morbidity and mortality [84–87]. It still remains to be transformed cystatin C values and the gold standard GFR,
elucidated whether there is a direct pathophysiological link which may be an acceptable but not a precise model in regard to
between cystatin C and cardiovascular disease as cystatin C is a the distribution of the variables. At present, the available data
potentially protective protein in the vessel wall in atherosclerosis are too preliminary to favor one equation over another, and
[88]. Alternatively, this association could be due to confounding these equations need to be vigorously evaluated in large diverse
cardiovascular risk factors such as reduced GFR, microinflamma- populations in multicenter studies.

Table 3
Cystatin C-based equations for the estimation of GFR in chronological order of their publication
Reference Equation Cystatin C GFR gold Population
assay standard
Equations for adults
51
[95] GFR = (78 / cystatin C [mg/L]) + 4 1 Cr-EDTA Renal transplant recipients (n = 25)
[40] GFR = (87.1 / cystatin C [mg/L]) − 6.87 2 Iohexol Adults (n = 40; 29 diabetics)
[49] GFR = (80.35 / cystatin C [mg/L]) − 4.32 1 125
I-iothalamate CKD patients (n = 123)
[93] GFR = 77.239 × cystatin C [mg/L]− 1.2623 1 Iohexol Adults (n = 100)
GFR = 99.434 × cystatin C [mg/L]− 1.5837 2 Iohexol Adults (n = 100)
[92] GFR = 99.19 × cystatin C [mg/L]− 1.713 × 0.823 (if female) 2 Iohexol Adults (n = 451)
[94] GFR = 87.62 × cystatin C [mg/L]− 1.693 × 0.94 (if female) 2 Iohexol Adults (n = 451)
[96] GFR = (86.7 / cystatin C [mg/L]) − 4.2 1 99m
-Tc-DTPA Diabetics (n = 251)
[35] GFR = 66.8 × cystatin C [mg/L]− 1.30 1 Iothalamate CKD patients (n = 357)
GFR = 76.6 × cystatin C [mg/L]−1.16 1 Iothalamate Renal transplant recipients (n = 103)

Equations for children

[39] GFR ≈ (162 / cystatin C [mg/L]) − 30 2 Inulin CKD patients (n = 184)
99m
[91] log GFR = 1.962 + [1.123 × log (1 / cystatin C [mg/L])] 1 -Tc-DTPA CKD patients (n = 536)
[94] GFR = 87.62 × cystatin C [mg/L]− 1.693 × 1.376 (if <14 years) × 0.94 (if female) 2 Iohexol Children (n = 85)
[97] GFR = 75.94 / cystatin C [mg/L]− 1.17 × 1.2(if renal transplant) 1 Iothalamate Children (n = 103)
1—immuno-nephelometric assay; 2—immuno-turbidimetric assay.
158 S. Herget-Rosenthal et al. / Clinical Biochemistry 40 (2007) 153–161

Comparison between cystatin C and creatinine-based measurements. Some of this variation can be attributed to the
prediction equations gold standard measurement itself [36]. The variation of ± 1.96
standard deviations in Bland–Altman plots amounts to ± 40%
In spite of these current obstacles, cystatin C-based equations [91] or ± 25 mL/min/1.73 m2 [49]. Levey et al. [18] showed that
for eGFR seem to be a promising alternative to creatinine-based the 90th percentile of the absolute difference between measured
ones. Several papers have compared cystatin C-based equations GFR by gold standard measurement and eGFR using the initial,
with the Schwartz [39,91,94,97], the Cockcroft–Gault seven-parameter MDRD equation was 30%. This explains, why
[35,49,68,92,96,98] and the simplified MDRD equations many studies comparing the performance of equations predicting
[35,68,94,96,98–100] and the majority found cystatin C-based GFR use the parameters “within 30% of measured gold standard
equations superior to creatinine-based equations as estimates of GFR” and “within 50% of measured GFR” [68,93,97,98,100].
GFR. When comparing bias, precision, accuracy and correlation Still, this is a significant improvement when compared to the
of cystatin C- with creatinine-based equations against gold predictive performance of an isolated serum creatinine measure-
standard measurements of GFR, which was not performed in all ment, and the reason why both the KDIGO and the KDOQI
studies despite being the current methodological standard, in the guidelines recommend the use of eGFR for the recognition and
majority of studies cystatin C-based equations performed better classification of CKD.
[49,68,91,92,94,97,98], while some showed no difference in the The limitations of creatinine, cystatin C, creatinine- and
performance of cystatin C- and creatinine-based equations cystatin C-based equations resulted in studies to provide novel
[35,39,96,99,100]. Especially the bias was lower, and to a lesser eGFR with lower bias and higher precision and accuracy.
extent precision and accuracy greater of cystatin C-based Recently, three eGFR equations were introduced which
equations towards measured GFR compared to creatinine- incorporate both serum creatinine and cystatin C [35,97,101].
based equations. Both Grubb et al. [92] and Hoek et al. [49] These equations performed better compared to the creatinine
observed an overestimation of GFR with the Cockcroft and and cystatin C-based equations in regard to bias, precision and
Gault equation while their respective cystatin C-based equations accuracy. Although not substantiated yet, this may indicate that
showed no bias. This was most pronounced in the recent study both serum cystatin C and creatinine could be complementary
by Pöge et al. in patients with liver cirrhosis [68]. Grubb et al. and not redundant in future equations estimating GFR.
[94] and Risch et al. [99] report overestimation of GFR by the
simplified MDRD equation, which could be corrected by a Summary, recommendations and perspective
factor to adjust for different creatinine assays. After adjustment,
the diagnostic efficiency to detect impaired renal function of Both creatinine and cystatin C measurement have to be
cystatin C and creatinine-based equations was comparable in improved by harmonization of methods and calibrators. As an
both studies. These findings underline the need for adequate isolated serum creatinine measurement bears a considerable
calibration before introduction of the MDRD equation into risk to misclassify kidney function, the eGFR calculated by the
clinical practice. Even after re-calibration, the simple MDRD MDRD or Cockcroft–Gault equations in adults and the
equation still needs three parameters in addition to serum Schwartz equations in children should be routinely calculated
creatinine whereas most cystatin C-based equations seem to by laboratories and issued along with creatinine measurements.
perform at least equally well without additional covariates. This may cause significant logistical problems as the additional
The marked heterogeneity of the cohorts, however, ranging data to perform the respective calculations (height, weight and
from infants to adults, from normal to markedly reduced GFR in ethnic background) are not routinely available in the
healthy subjects, CKD and renal transplant recipients, of the laboratory. Here the use of cystatin C-based equations, which
gold standard GFR measurements, and the diversity of cystatin
C-based equations (Table 3) do not permit a definite conclusion
whether these equations are superior. In addition, few studies Table 4
Recommendations for the differentiated use of markers to detect reduced GFR at
have yet been tested these equations in patient cohorts different various stages of chronic kidney disease and in acute kidney injury
from those in which the cystatin C-based equation was derived
GFR Detection marker Specific indication
from thus not favoring cystatin C in their analysis [68,98–100].
[mL/min/1.73 m2]
At present, clinicians should not overestimate eGFR calculated
60–90 Serum cystatin C
from cystatin C-based equations, as many limitations of the
20–60 MDRD equation In adults
creatinine-based equations, e.g., moderate precision, also apply Cockcroft–Gault equation In adults
to them. Schwartz equation In children
Serum cystatin C BMI >30 kg/m2, nephrotic
Precision of cystatin C and creatinine-based equations syndrome, acute kidney
injury superimposed on CKD
estimating GFR
<20 (Creatinine clearance + urea
clearance) / 2
Looking at the precision of eGFR calculation with all the Acute kidney Serum cystatin C
equations developed so far – both the creatinine-based and injury
cystatin C-based equations – one has to realize the wide scatter CKD, chronic kidney disease; MDRD, Modification of Diet in Renal Disease
of the eGFR values around the respective gold standard Study.
 S. Herget-Rosenthal et al. / Clinical Biochemistry 40 (2007) 153–161 159

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60 mL/min/1.73 m2 (Table 4). With GFR above 60 mL/min/
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